The long-term goal of our research is to understand the neural circuit basis of learning and memory. In this project, we aim to understand how neural circuits process and store temporal sequence information in the sensory experience. We propose to test the specific hypothesis that spike timing-dependent plasticity (STDP) of intracortical connections provides a mechanism for cortical circuits to perform sequence learning. The hypothesis is based on our preliminary finding that repetitive visual conditioning with uni-directional moving spot in the visual field of either anesthetized or awaked rats resulted in sequential spiking of a specific ensemble of V1 neurons with adjacent receptive fields along the path of the moving spot, and this neuronal ensemble retained the memory of sequential spiking, as manifested by post-conditioning evoked and spontaneous sequential spiking of the ensemble. To test our hypothesis, we propose to carry out experiments on head-fixed awake and anesthetized rats, using a combination of in vivo techniques that include multielectrode array recording, voltage-sensitive dye imaging (VSDI), in vivo whole-cell recording, and optogenetic neuronal activation. In Aim 1, we will confirm and characterize the phenomenon of sequence learning and recall/replay and determine the optimal parameters of visual conditioning in inducing sequence learning/memory, as monitored by the multielectrode array and VDSI of cortical activity waves. In Aim 2, we will determine whether conditioning visual stimuli can indeed induce synaptic modification of intracortical excitatory connections in a manner consistent with STDP, and whether the induction and expression mechanisms of visual conditioning-induced synaptic changes are similar to STDP induced by repetitive pre- and postsynaptic neuronal spiking. In Aim 3, we will determine whether STDP is necessary for visual conditioning-induced sequence learning and sufficient by itself for inducing sequence memory in the V1. Together, this project will provide new insights into the synaptic and circuit mechanisms by which temporal sequence information may be coded and stored by cortical circuits. It will also advance our understanding of the properties of STDP in vivo and its role in learning and memory functions. PUBLIC HEALTH RELEVANCE: The temporal sequence of events is a critical element in learning and memory. This project will provide new insights into the synaptic and circuit mechanisms in the cortex underlying sequence learning and memory.